In view of its strategic position at the termini of the two major pathways of glucose production in the liver and kidneys of higher animals, the glucose-6-phosphatase system warrants serious consideration as a potential site to effect clinical management of the hyperglycemia associated with diabetes mellitus. The proposed project is designed to explore the feasibility and potential of intervention at the level of glucose-6-phosphate hydrolysis and to provide a characterization of the components of the glycose-6-phosphatase system in molecular terms. The project involves the following studies: (1) the characterization of the glucose-6-phosphatase systems in liver microsomes of several species to find the best model for the human enzyme; (2) a definitive appraisal of the postulated involvement of a glucose-6-phosphate translocase in the function of the enzyme; (3) the purification and characterization of the individual components of the functional glucose-6-phosphatase system; and (4) characterization of the catalytic and regulatory properties of glucose-6-phosphatase in situ employing isolated liver parenchymal cells and perfused livers.